WO2004027047A2 - Inhibiteurs de 11$g(b)-hydroxysteroide dehydrogenase et leurs utilisations - Google Patents

Inhibiteurs de 11$g(b)-hydroxysteroide dehydrogenase et leurs utilisations Download PDF

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WO2004027047A2
WO2004027047A2 PCT/US2003/030017 US0330017W WO2004027047A2 WO 2004027047 A2 WO2004027047 A2 WO 2004027047A2 US 0330017 W US0330017 W US 0330017W WO 2004027047 A2 WO2004027047 A2 WO 2004027047A2
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hydroxysteroid dehydrogenase
inhibitor
cortisol
formula
cortisone
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PCT/US2003/030017
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WO2004027047A3 (fr
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Hartmut M. Hanauske-Abel
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Hanauske-Abel Hartmut M
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Publication of WO2004027047A3 publication Critical patent/WO2004027047A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine

Definitions

  • the present invention relates to natural and man-made inhibitors of the 1 l ⁇ -hydroxysteroid dehydrogenase enzymes that modulate glucocorticoid bioactivity in vivo by catalyzing either the formation of cortisol by reduction of cortisone, or the removal of cortisol by oxidation to cortisone.
  • the inhibitors of the present invention can be used to treat inflammatory and allergic conditions, cancer, and several metabolic syndromes.
  • Cortisol the major glucocorticoid (GC)
  • GC glucocorticoid
  • Cortisol a steroid hormone
  • Cortisol is synthesized de novo in the adrenal gland and secreted into the bloodstream, from where it reaches all the tissues and cells of the human body. This fact does not imply that all tissues and cells see the same amount of cortisol, however, nor does it imply that cortisol can become biologically available by de novo synthesis only.
  • the actual bioavailability of GCs like cortisol at the level of individual cells is not merely a function of their concentration in blood, nor of their binding to plasma proteins, nor of the varying densities of steroid hormone receptors in target tissues.
  • the actual bioavailability and bioactivity of GCs, even at the level of individual hormone receptors inside of a cell, is controlled by pre- receptor metabolism of the GCs, mediated by cell and tissue specific enzymes that locally activate or deactivate GCs. Consequently, tissue GC levels do not merely reflect plasma GC levels.
  • the 1 l ⁇ -hydroxysteroid dehydrogenases (1 IB HSDs) are the most prominent enzymes functioning in pre-receptor metabolism.
  • the 1 IB HSD activity occurs in two isoforms, 1 IB HSD1 and 1 IB HSD2, the former encoded on chromosome 1, the latter on chromosome 16.
  • 1 IB HSD1 catalyses, when tested in vitro, either: i) the inactivation of cortisol, by oxidation of the 1 IB OH group using NADP as cofactor and generating biologically inert cortisone; or ii) the generation of cortisol, by reduction of the 11 keto group of cortisone using NADPH as cofactor. In vivo, this isoform prefers the reductase direction, i.e.
  • 1 IB HSD1 In the brain, the lack of 1 IB HSD1 activity ameliorates age-related learning impairments, and selective inhibitors of 1 IB HSD1 have been proposed to be useful agents for preventing glucocorticoid-associated learning deficits (Yau et al., Proc. Natl. Acad. USA 98:4716-4721 (2001) and references therein).
  • Local modification of GC bioactivity by 1 IB HSD1 has also been established to occur in numerous other tissues, exemplified by, but not limited to, blood vessel wall, ovary, eye, lymph node, and lung (Stewart et al., Vitam. Horm.
  • 1 IB HSD1 can amplify glucocorticoid target gene expression in key sites that control metabolic fuel utilization, enhanced 1 IB HSD1 activity is important in increasing local glucocorticoid action and promoting adverse metabolic effects.
  • Tissue-specific patterns of 1 IB HSD1 deregulation are now well recognized and appear to be causal for major human ailments, exemplified by the metabolic syndrome and by human obesity, in which a substantial enhancement of 1 IB HSD1 activity in adipose tissue has been documented that suffices to amplify glucocorticoid action locally (Rask et al. J. Clin. Endocrinol. Metab. 87:3330- 3336 (2002) and references therein). Consequently, inhibition of adipose 1 IB HSD1 was identified as an exciting target for future drug treatment that aims at reducing GC effects in fat by limiting tissue-specific GC reactivation.
  • 1 IB HSD2 catalyses exclusively the inactivation of GCs like cortisol, from which it generates cortisone by oxidizing the 1 IB OH group to an 11 keto group.
  • 1 IB HSD2 only uses NAD as cofactor. This isoform can function as a dehydrogenase even at cortisol concentrations in the nm range. In this way, 1 IB HSD2 provides a highly efficient, constitutive barrier against GC access to steroid hormone receptors that interact with either GCs or mineralocorticoids (MCs), mediating their respective biological effects.
  • MCs mineralocorticoids
  • the shielding of the mineralocorticoid receptor (MR) is particularly important, since GC and MC bind to this receptor with equally high affinity in vitro, whereas in vivo only MCs are able to activate the MR, despite the 100- to 1000-fold excess of GCs.
  • 1 IB HSD2 protects the MR from illicit activation. Mutations of 1 IB HSD2 in man and mice have established that in case of a genetic deficiency, the loss of receptor protection leads to a severe condition.
  • GCs are now able to overwhelm and over-activate the MR, particularly in the kidney, and in this way cause the Syndrome of Apparent Mineralocorticoid Excess (SAME), which is characterized by hypertension, hypernatremia, hypokalemia, and other potentially life-threatening abnormalities (Holmes et al., Mol. Cell Endocrinol. 171:15-20 (2001) and references therein).
  • SAME Apparent Mineralocorticoid Excess
  • 11B HSD2 is expressed in a stringent manner in all mineralocorticoid tissues, including the kidneys.
  • 1 IB HSD2-catalyzed GC inactivation also has significant biological roles in various other tissues.
  • 1 IB HSD2 is also able to affect the function of the GC receptor and consequently, the expression of GC- controlled genes.
  • the significantly increased expression and activity of 1 IB HSD2 in cancer cells is actually further induced by GCs of endogenous or exogenous origin, which accelerate their intracellular catabolism and impair their own antiproliferative effect.
  • 1 IB HSD2 provides an enzymatic shield that protects these malignantly proliferating cells, e.g. of breast origin, from the antiproliferative effects of GC. Consequently, inhibition of the inactivating 1 IB HSD2 should markedly enhance the antiproliferative activity of GC.
  • GCs were found to indeed inhibit cancer cell proliferation, suggesting inhibition of 1 IB HSD2 activity in tumor cells retards tumor growth by locally increasing the bioavailability of GCs, whether of endogenous or exogenous origin (Hundertmark et al., J. Endocrinol. 155:171-180 (1997) and references therein).
  • the anti-inflammatory activity of GCs can be markedly enhanced by combination with the experimental 1 IB HSD2 inhibitor glycyrrhetinic acid, as shown for contact hypersensitivity of skin using topical application of the compound combination (Hennebold et al., Arch.
  • the present invention is directed to overcoming these and other deficiencies in the art.
  • the present invention relates to a method of inhibiting 11 ⁇ - hydroxysteroid dehydrogenase in a living system.
  • This method involves administering to the living system an effective amount of an inhibitor of cortisol- to-cortisone conversion, as mediated by 11 ⁇ -hydroxy steroid dehydrogenase, of formula I or an inhibitor of cortisone-to-cortisol conversion, as mediated by 11 ⁇ - hydroxysteroid dehydrogenase, of formula II or derivatives thereof as follows:
  • R is H or CH 3
  • R 2 is H, CH 3 , or CH 2 CH 3
  • R 3 is H, CH 3 , CH 2 CH 3 , or CH 2 CH 2 CH 3
  • R 4 is H, CH 3 , or CH 2 CH 3
  • R 5 is H, CH 3 , or CH 2 CH 3
  • Re is H, CH 3 , CH 2 CH 3 , or CH 2 CH 2 CH 3
  • R 7 is H or CH 3
  • X is OH, SH, or NH 2
  • X' is O, S, or NH
  • Y is O, S, NH, or CH 2 .
  • the present invention also relates to a method of inhibiting 11 ⁇ - hydroxysteroid dehydrogenase in a living system.
  • This method involves administering to the living system an effective amount of an inhibitor of cortisol- to-cortisone conversion, as mediated by 1 l ⁇ -hydroxysteroid dehydrogenase, of formula III or an inhibitor of cortisone-to-cortisol conversion, as mediated by 1 l ⁇ - hydroxysteroid dehydrogenase, of formula IV or derivatives thereof as follows:
  • R 6 is O or S and R 7 is H, OH, or halogen, or
  • R 8 is H, OH, or halogen
  • R 9 is H, OH, or halogen
  • R 3 is OH, SH, or NH 2
  • R 3 ' is O, S, or NH
  • R is O, S, NH, or CH 2
  • R 5 is N or CH 2
  • R 5 ' is SO or CH 2 .
  • Another aspect of the present invention relates to a method of inhibiting 1 l ⁇ -hydroxysteroid dehydrogenase in a living system.
  • This method involves administering to the living system an effective amount of an inhibitor of cortisol-to-cortisone conversion, as mediated by 1 l ⁇ -hydroxysteroid dehydrogenase, of formula V or an inhibitor of cortisone-to-cortisol conversion, as mediated by 11 ⁇ -hydroxy steroid dehydrogenase, of formula VI or derivatives thereof as follows:
  • R 2 is H, OH, or halogen
  • R 3 is OH, SH, or NH 2
  • R 3 ' is O, S, or NH
  • R 4 is O, S, NH, or CH 2
  • R 5 is N or CH 2
  • R 5 ' is SO or CH 2 .
  • Yet another aspect of the present invention relates to a method of inhibiting 1 l ⁇ -hydroxysteroid dehydrogenase in a living system.
  • This method involves administering to the living system an effective amount of an inhibitor of cortisol-to-cortisone conversion, as mediated by 11 ⁇ -hydroxysteroid dehydrogenase, of formula VII or an inhibitor of cortisone-to-cortisol conversion, as mediated by 11 ⁇ -hydroxysteroid dehydrogenase, of formula VIII or derivatives thereof as follows:
  • R 2 is H, OH, or halogen
  • R 3 is OH, SH, or NH 2
  • R 3 ' is O, S, or NH
  • R is O, S, NH, or CH 2
  • R 5 is N or CH 2
  • R 5 ' is SO or CH 2 .
  • Additional aspects of the present invention relate methods of treating an inflammatory or allergic condition, cancer, obesity, diabetes mellitus, or a metabolic syndrome involving 1 l ⁇ -hydroxysteroid dehydrogenase in a living system. These methods involve administering to the living system an inhibitor of cortisol-to-cortisone conversion, as mediated by 11 ⁇ -hydroxysteroid dehydrogenase, of formula I, III, V, or VII, or an inhibitor of cortisone-to-cortisol conversion, as mediated by 11 ⁇ -hydroxysteroid dehydrogenase, of formula II, IV, VI, or VIII, or derivatives thereof as described above under conditions effective to treat an inflammatory or allergic condition, cancer, obesity, diabetes mellitus, or a metabolic syndrome involving 11 ⁇ -hydroxysteroid dehydrogenase.
  • 1 l ⁇ HSD have been identified based on the identification of the minimally required structure for interaction with 1 l ⁇ HSD.
  • these inhibitors can be used in methods of treating an inflammatory or allergic condition, cancer, obesity, diabetes mellitus, or a metabolic syndrome involving 1 l ⁇ -hydroxysteroid dehydrogenase in a living system.
  • Figure 1 shows the steric structure of two 1 IB HSD substrates, the glucocorticoids cortisol and corticosterone, and two isomers of menthol, (IS, 2S, 5R)-neomenthol and (IS, 2R, 5R)-isomenthol. Note the sterically distinct, axial vs. equatorial substitution at C2 of the menthol isomers. Only neomenthol mirrors precisely onto the glucocorticoids, extending from ring A over ring B to ring D, with a complete fit at ring C. Neomenthol exactly mimics the steric arrangement at carbon atoms 1, 10, 19, 9, 11, 12, 13, and 17.
  • FIG. 2 shows the computational analysis and visualization of cortisol [ I ], (IS, 2S, 5R)-neomenthol [ II ] and (IS, 2R, 5R)-isomenthol [ III ] ⁇ axial line of view.
  • the white line bracket highlights the area of homology, centering on the oxygen atom at C 11, the subject of the redox activity of 1 IB HSD.
  • An arrow indicates the relevant proton. *, position of the C19 methyl moiety or equivalent; white arrow, substrate proton of 1 IB HSDs; solid isosurfaces: 0.08 electrons/au 3 ; dotted isosurfaces, 0.002 electrons/au 3 ; electrostatic potential gray-shaded onto each isosurface. Note the marked difference between neomenthol and isomenthol when compared with cortisol.
  • FIG. 3 shows the computational analysis and visualization of cortisol [ I ], (IS, 2S, 5R)-neomenthol [ II ] and (IS, 2R, 5R)-isomenthol [ III ] ⁇ equatorial line of view.
  • the white line bracket highlights the area of homology, centering on the oxygen atom at C 11, the subject of the redox activity of 1 IB HSD.
  • An arrow indicates the relevant proton. *, position of the C19 methyl moiety or equivalent; white arrow, substrate proton of 1 IB HSDs; solid isosurfaces: 0.08 electrons/au ; dotted isosurfaces, 0.002 electrons/au ; electrostatic potential gray-shaded onto each isosurface. Note the marked difference between neomenthol and isomenthol when compared with cortisol.
  • Figure 4 is a Lineweaver-Burk plot, and its secondary plot, of corticosterone utilization by rat liver 1 IB HSD (oxidative activity) in the presence of increasing concentrations of (IS, 2S, 5R)-(+) neomenthol. The concentrations of the inhibitor are indicated. The mode of inhibition is competitive, indicating that this menthol isomer binds precisely like the GC substrate to 1 IB HSD (see 84 th Annual Meeting, Endocrine Society; p273 (#P1-516) (2002)).
  • Figure 5 is a Lineweaver-Burk plot, and its secondary plot, of corticosterone utilization by rat liver 1 IB HSD (oxidative activity) in the presence of increasing concentrations of (IS, 2R, 5R)-isomenthol. The concentrations of the inhibitor are indicated. The mode of inhibition is non-competitive, indicating that this menthol isomer does not bind like the GC substrate to 1 IB HSD (see 84 th Annual Meeting, Endocrine Society; ⁇ 273 (#P1-516) (2002)).
  • Figure 6 shows the structure of the 1 IB HSD substrates cortisol and cortisone, and the small molecule conformation homologues, (IS, 2S, 5R)- neomenthol and (2R, 5R)-neomenthone, respectively.
  • the monoterpene conformation homologues mirrors precisely onto cortisol and cortisone, extending from ring A over ring B to ring D, with a complete fit at ring C. Their conformation therefore makes them suitable lead compounds for improved small molecule inhibitors that modulate in vivo the activity of 1 IB HSD2 and of 1 IB HSD1, respectively.
  • Figure 7 shows the structural formulae (top and bottom), and computationally generated composite surfaces (left, isodensity surface at 0.08 electrons/au 3 ; middle, isodensity surface at 0.002 electrons/au 3 ; right, ball-and- stick model; electrostatic potential gray-shaded onto each isosurface; fine dots, electrostatic potential cloud at 20 kcal/mol) for cortisol (compound I) and for neomenthol (compound II).
  • Figure 8 shows structural formulae (top and bottom), and computationally generated composite surfaces (left, isodensity surface at 0.08 electrons/au 3 ; middle, isodensity surface at 0.002 electrons/au 3 ; right, ball-and- stick model; electrostatic potential gray-shaded onto each isosurface; fine dots, electrostatic potential cloud at 20 kcal/mol) for cortisol (compound I) and for compound III.
  • Figure 9 shows structural formulae (top and bottom), and computationally generated composite surfaces (left, isodensity surface at 0.08 electrons/au ; middle, isodensity surface at 0.002 electrons/au ; right, ball-and- stick model; electrostatic potential gray-shaded onto each isosurface; fine dots, electrostatic potential cloud at 20 kcal/mol) for cortisol (compound I) and for compound IV.
  • Figure 10 shows structural formulae (top and bottom), and computationally generated composite surfaces (left, isodensity surface at 0.08 electrons/au 3 ; middle, isodensity surface at 0.002 electrons/au 3 ; right, ball-and- stick model; electrostatic potential gray-shaded onto each isosurface; fine dots, electrostatic potential cloud at 20 kcal/mol) for cortisol (compound I) and for compound V.
  • Figure 11 shows the proposed dual action of neomenthol, facilitating release of plasma protein-bound and therefore biologically unavailable cortisol while at the same time, inhibiting the cortisol-to-cortisone dehydrogenation (cortisol inactivation) mediated by 1 IB HSD activity.
  • the local effect amounts to an increase in the bioavailable cortisol and thus, to locally enhanced biological effects of cortisol and similar glucocorticoids (see 84 th Annual Meeting, Endocrine Society; p273 (#P1-516) (2002)).
  • the present invention relates to a method of inhibiting 11 ⁇ - hydroxysteroid dehydrogenase in a living system.
  • This method involves administering to the living system an effective amount of an inhibitor of cortisol- to-cortisone conversion, as mediated by 11 ⁇ -hydroxysteroid dehydrogenase, of formula I or an inhibitor of cortisone-to-cortisol conversion, as mediated by 1 l ⁇ - hydroxysteroid dehydrogenase, of formula II or derivatives thereof as follows:
  • R x is H or CH 3
  • R 2 is H, CH 3 , or CH 2 CH 3
  • R 3 is H, CH 3 , CH 2 CH 3 , or CH 2 CH 2 CH 3
  • R 4 is H, CH 3 , or CH 2 CH 3
  • R 5 is H, CH 3 , or CH 2 CH 3
  • Rg is H, CH 3 , CH 2 CH 3 , or CH 2 CH 2 CH 3
  • R 7 is H or CH 3
  • X is OH, SH, or NH 2
  • X' is O, S, or NH
  • Y is O, S, NH, or CH 2 .
  • the inhibitor has the formula:
  • the inhibitor has the formula:
  • the present invention also relates to a method of inhibiting 11 ⁇ - hydroxysteroid dehydrogenase in a living system.
  • This method involves administering to the living system an effective amount of an inhibitor of cortisol- to-cortisone conversion, as mediated by 11 ⁇ -hydroxysteroid dehydrogenase, of formula III or an inhibitor of cortisone-to-cortisol conversion, as mediated by 1 l ⁇ - hydroxysteroid dehydrogenase, of formula IV or derivatives thereof as follows:
  • R 6 is O or S and R 7 is H, OH, or halogen, or
  • R 8 is H, OH, or halogen
  • R 9 is H, OH, or halogen
  • R 3 is OH, SH, or NH 2
  • R 3 ' is O, S, or NH
  • R 4 is O, S, NH, or CH 2
  • R 5 is N or CH 2
  • R 5 ' is SO or CH 2 .
  • Another aspect of the present invention relates to a method of inhibiting 1 l ⁇ -hydroxysteroid dehydrogenase in a living system.
  • This method involves administering to the living system an effective amount of an inhibitor of cortisol-to-cortisone conversion, as mediated by 1 l ⁇ -hydroxysteroid dehydrogenase, of formula V or an inhibitor of cortisone-to-cortisol conversion, as mediated by 11 ⁇ -hydroxysteroid dehydrogenase, of formula VI or derivatives thereof as follows:
  • R 2 is H, OH, or halogen
  • R 3 is OH, SH, or NH 2
  • R 3 ' is O, S, or NH
  • R 4 is O, S, NH, or CH 2
  • R 5 is N or CH 2
  • R 5 ' is SO or CH 2 .
  • Yet another aspect of the present invention relates to a method of inhibiting 11 ⁇ -hydroxysteroid dehydrogenase in a living system.
  • This method involves administering to the living system an effective amount of an inhibitor of cortisol-to-cortisone conversion, as mediated by 11 ⁇ -hydroxy steroid dehydrogenase, of formula VII or an inhibitor of cortisone-to-cortisol conversion, as mediated by 11 ⁇ -hydroxysteroid dehydrogenase, of formula VIII or derivatives thereof as follows:
  • R 2 is H, OH, or halogen
  • R 3 is OH, SH, or NH 2
  • R 3 ' is O, S, or NH
  • R4 is O, S, NH, or CH 2
  • R 5 is N or CH 2
  • R 5 ' is SO or CH 2 .
  • the inhibitors of the present invention inhibit isoform I of 11 ⁇ HSD.
  • the inhibitors of the present invention inhibit isoform II of 11 ⁇ HSD.
  • suitable living systems include, but are not limited to, mammals, including dogs, cats, rats, mice, and humans, and non-mammalian species like fish or insects.
  • Suitable derivatives of the above-identified inhibitors include, but are not limited to, esters, amides, and their salts.
  • One of the most productive strategies for the discovery of an enzyme inhibitor involves the identification of the minimally required structure able to bind to, and thus be a substrate for or an inhibitor of, the enzyme of interest. This is followed by the knowledge-guided formulation of a series of optimized analogs and derivatives, applying structural principles of molecular pharmacology that are known to those trained in the art (see, e.g., Hanauske-Abel et al., Curr. Med. Chem. 10:1005-1019 (2003) for a description of a successful application of this strategy to the discovery of lead compounds for inhibition of enzymes that hydroxylate proteins).
  • Synthesis of the compounds of the present invention can be achieved using methods known to those of ordinary skill in the art.
  • the compounds of the present invention can be synthesized retrosynthetically, based on the identification of the optimal structures for inhibitors in accordance with the present invention, as pathways to produce the desired compounds would be obvious to one of ordinary skill in the chemical arts.
  • Synthesis can be carried out either manually or through the use of an automated process.
  • the chemical manipulations would be performed by a scientist or technician.
  • the chemical manipulations would typically be performed robotically. The choice and implementation of such techniques is within the skill of one of ordinary skill in the chemical arts and will not be discussed in detail herein.
  • Additional aspects of the present invention relate methods of treating an inflammatory or allergic condition, cancer, obesity, diabetes mellitus, or a metabolic syndrome involving 1 l ⁇ -hydroxysteroid dehydrogenase in a living system. These methods involve administering to the living system an inhibitor of cortisol-to-cortisone conversion, as mediated by 1 l ⁇ -hydroxysteroid dehydrogenase, of formula I, III, V, or VII, or an inhibitor of cortisone-to-cortisol conversion, as mediated by 11 ⁇ -hydroxysteroid dehydrogenase, of formula II, IV, VI, or VIII, or derivatives thereof as described above under conditions effective to treat an inflammatory or allergic condition, cancer, obesity, diabetes mellitus, or a metabolic syndrome involving 1 l ⁇ -hydroxysteroid dehydrogenase.
  • inflammatory or allergic conditions include, but are not limited to, acute or chronic conditions caused or aggravated by the activation and involvement of humoral and/or cellular elements of the immune system in response to exogenous or endogenous triggers.
  • dermatological conditions such as hypersensitivity reactions and allergies; pulmonary conditions such as asthma; gastrointestinal conditions such as ulcerative colitis; and systemic conditions such as multiple sclerosis or rheumatoid arthritis; as well as rejection of transplants.
  • metabolic syndromes involving 11 ⁇ - hydroxysteroid dehydrogenase include, but are not limited to obesity, diabetes mellitus, and the various conditions involving insulin resistance, such as ovarian hyperandrogenism or Syndrome X .
  • the inhibitor of the present invention can be administered alone, or in combination with suitable pharmaceutical carriers or diluents.
  • suitable pharmaceutical carriers or diluents should be selected so that they do not diminish the therapeutic effects of the inhibitors of the present invention or compositions.
  • Suitable pharmaceutical compositions include those which include a pharmaceutical carrier and, for example, one or more of an inhibitor, as described herein.
  • a pharmaceutically acceptable medium can additionally contain physiologically acceptable compounds that act, for example, to stabilize or increase the absorption of the inhibitor of the present invention, analogue, mimetic, or chemical derivative.
  • physiologically acceptable compounds include, for example, carbohydrates such as glucose, sucrose, or dextrans; antioxidants such as ascorbic acid or glutathione; chelating agents such as EDTA, which disrupts microbial membranes; divalent metal ions such as calcium or magnesium; low molecular weight proteins; lipids or liposomes; or other stabilizers or excipients.
  • the inhibitors of the present invention and compositions herein can be made up in any suitable form appropriate for the desired use; e.g., oral, parenteral, or topical administration.
  • topical and/or system administration may be used.
  • parenteral administration are intraventricular, intracerebral, intranasal, intraocular, intramuscular, intravenous, intraarterial, intraperitoneal, by intraversal instillation, intralesion, rectal, and subcutaneous administration. Administration may also be achieved by application to mucous membranes.
  • Suitable dosage forms for oral use include tablets, dispersible powders, granules, capsules, suspensions, syrups, and elixirs.
  • Inert diluents and carriers for tablets include, for example, calcium carbonate, sodium carbonate, lactose, and talc. Tablets may also contain granulating and disintegrating agents, such as starch and alginic acid; binding agents, such as starch, gelatin, and acacia; and lubricating agents, such as magnesium stearate, stearic acid, and talc. Tablets may be uncoated or may be coated by known techniques to delay disintegration and absorption. Inert diluents and carriers which may be used in capsules include, for example, calcium carbonate, calcium phosphate, and kaolin.
  • Suspensions, syrups, and elixirs may contain conventional excipients, such as methyl cellulose, fragacanth, sodium alginate; wetting agents, such as lecithin and polyoxyethylene stearate; and preservatives, such as ethyl-p-hydroxybenzoate.
  • excipients such as methyl cellulose, fragacanth, sodium alginate
  • wetting agents such as lecithin and polyoxyethylene stearate
  • preservatives such as ethyl-p-hydroxybenzoate.
  • Dosage forms suitable for parenteral administration include solutions, aqueous and non-aqueous suspensions which can include suspending agents and thickening agents, dispersions, emulsions, and the like. They may also be manufactured in the form of sterile solid compositions which can be dissolved or suspended in sterile injectable medium immediately before use. They may contain suspending or dispersing agents known in the art.
  • the solutions, suspensions, dispersions, emulsions, and the like can additionally contain, for example, anti-oxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient.
  • the formulations can be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
  • solid or fluid unit dosage forms can be prepared.
  • a suitable inhibitor of the present invention or composition, as disclosed above is mixed with conventional ingredients, such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia methylcellulose, and functionally similar materials as pharmaceutical diluents or carriers.
  • Capsules are prepared by mixing the disclosed inhibitors of the present invention or compositions with an inert pharmaceutical diluent and filling the fixture into a hard gelatin capsule of appropriate size.
  • Soft gelatin capsules are prepared by machine encapsulation of a slurry of the inhibitor of the present invention or composition with an acceptable vegetable oil, light liquid petrolatum, or other inert oil.
  • Fluid unit dosage forms for oral administration such as syrups, elixirs, and suspensions can be prepared.
  • the water-soluble forms can be dissolved in an aqueous vehicle together with sugar, aromatic flavoring agents, and preservatives to form a syrup.
  • An elixir is prepared by using a hydro- alcoholic (ethanol) vehicle with suitable sweeteners, such as sugar and saccharin, together with an aromatic flavoring agent.
  • Suspensions can be prepared with a syrup vehicle with the aid of a suspending agent, such as acacia, fragacanth, methylcellulose, and the like.
  • suitable daily dosages can be based on suitable doses of glucocorticoids, such as those described in Goodman and Gilman, The
  • suitable daily doses are from about 0.5 mg d to about 60 mg/d of the inhibitor of the present invention for adult patients, with proper adjustments for the spectrum of pediatric patients.
  • the inhibitors of the present invention or compositions can be administered orally in foodstuffs.
  • fluid unit dosage forms are prepared utilizing the aforementioned inhibitors of the present invention or compositions and a sterile vehicle, water being preferred.
  • the inhibitor of the present invention or composition depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the inhibitor of the present invention or composition can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampule and sealing.
  • adjuvants such as a local anesthetic, preservative, and buffering agents, can be dissolved in the vehicle.
  • the fluid unit dosage form can be frozen after filling into the vial, and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial, and an accompanying vial of water for injection is supplied to reconstitute the liquid prior to use.
  • Parenteral suspensions are prepared in substantially the same manner except that the inhibitor of the present invention or composition is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration.
  • the inhibitor of the present invention or composition can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the parenteral suspension to facilitate uniform distribution of the inhibitor of the present invention or composition.
  • Parenteral dosages typically can range from about 0.5 mg/d to about 500 mg/d of the inhibitor of the present invention for adult patients, with proper adjustments for the spectrum of pediatric patients.
  • the inhibitor of the present invention or composition can be used in polymeric formulations and sustained release formulations and surgically implanted using conventional methods.
  • Suitable sustained release matrices include those made of ethylene vinyl acetate and other biocompatible polymers.
  • the inhibitor of the present invention can be covalently attached by surface grafting or co-polymerization, non-covalently incorporated into a matrix, or otherwise encapsulated as biomedical materials. This is one example of a drug delivery method involving conjugation of the inhibitor of the present invention to a carrier material that can be used to locally deliver the anti-1 l ⁇ -hydroxysteroid dehydrogenase effects of such a formulation.
  • carriers such as phospholipid vesicles, which contain the aforementioned inhibitor of the present invention or composition may facilitate uptake through the skin.
  • Molecules of interest were build from the atomic fragment catalog of the Spartan software package (Wavefunction, Irvine, CA). Molecular mechanics analysis was performed with both the semi-empirical AMI menu and ab initio Hartree-Fock calculations using the 3-21G :
  • the purified rat liver 1 IB HSD when used in vitro, utilizes NADP+ and oxidizes cortisol and corticosterone in an ordered sequential bireactant mechanism (Monder et al., Biochim. Biophys. Ada 1115:23-29 (1991) and references therein). Employing l,2,6,7- 3 H-corticosterone, neomenthol, and isomenthol inhibited the enzyme.
  • Figure 9 details the findings for a representative compound in which, among other modifications, a ring has been added to the structure equivalent to the D ring of cortisol.
  • Figure 10 details the findings for a representative compound in which, among other modifications, a structure equivalent to the D ring of cortisol has been deleted.
  • these structures are sufficiently isosteric and isoelectronic with cortisol to displace it from its plasma binding proteins, in this way increasing the bioavailable, free cortisol in a living system, e.g. after topical administration to skin only in skin blood vessels.

Abstract

L'invention concerne l'identification d'inhibiteurs naturels et artificiels des enzymes 11ß-hydroxystéroïde déhydrogénase, lesquels modulent la bioactivité glucocorticoïde in vivo en catalysant la formation de cortisole par réduction de cortisone ou l'élimination de cortisole par oxydation en cortisone. Cette façon de moduler la bioactivité glucocorticoïde in vivo est d'importance pour les états inflammatoires et les allergies, le cancer et différents syndromes métaboliques.
PCT/US2003/030017 2002-09-18 2003-09-18 Inhibiteurs de 11$g(b)-hydroxysteroide dehydrogenase et leurs utilisations WO2004027047A2 (fr)

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AU2003275195A AU2003275195A1 (en) 2002-09-18 2003-09-18 INHIBITORS OF 11Beta-HYDROXYSTEROID DEHYDROGENASE AND USES THEREFOR

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US60/411,622 2002-09-18

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WO2006097337A2 (fr) * 2005-03-18 2006-09-21 Onepharm Gmbh Inhibiteurs de la 11$g(b)-hydroxysteroide deshydrogenases
WO2007025892A1 (fr) 2005-08-31 2007-03-08 F. Hoffmann-La Roche Ag Inhibiteur de la 11-bêta-hydroxystéroïde déhydrogénase-1 des diabètes de type 2-1
WO2010047982A1 (fr) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Nouveaux dérivés de benzimidazole cycliques utiles comme agents anti-diabétiques
WO2010051206A1 (fr) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Nouveaux agents antidiabétiques utiles avec des dérivés de benzimidazole cycliques
US7759339B2 (en) 2005-03-31 2010-07-20 Takeda San Diego, Inc. Hydroxysteroid dehydrogenase inhibitors
WO2011106273A1 (fr) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Nouveaux dérivés benzimidazole cycliques utiles comme agents antidiabétiques
WO2012116145A1 (fr) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
WO2014022528A1 (fr) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2014130608A1 (fr) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Composés bicycliques antidiabétiques
WO2014139388A1 (fr) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Nouveaux dérivés d'indole utiles en tant qu'agents antidiabétiques
WO2015051725A1 (fr) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2018106518A1 (fr) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Composés hétérocycliques antidiabétiques
WO2018118670A1 (fr) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Composés de spirochromane antidiabétiques
WO2019186171A1 (fr) * 2018-03-28 2019-10-03 Benevolentai Bio Limited Traitement des maladies sarcopéniques
EP3878446A1 (fr) 2020-03-09 2021-09-15 Universite De Geneve Inhibiteurs hsd11b1 pour utilisation en immunothérapie et leurs utilisations

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EP1587574A4 (fr) * 2001-12-21 2009-03-18 Rhode Island Hospital INHIBITEURS SELECTIFS DE 11b-HSD ET LEURS PROCEDES D'UTILISATION
US20060159622A1 (en) * 2003-02-21 2006-07-20 Koo Gloria C Pharmacodynamic assay for inhibitors of 11-beta-hydroxysteroid dehydrogenase activity in animal tissues
WO2004097002A2 (fr) * 2003-04-29 2004-11-11 The Miriam Hospital Inhibiteurs 11?-hsd de testosterone selectifs et methodes d'utilisation
US7629413B2 (en) * 2005-01-18 2009-12-08 Exxonmobil Chemical Patents Inc. Plasticiser compositions
US20210030802A1 (en) * 2018-04-07 2021-02-04 Constant Biotechnology, Llc Glucocorticoid-resistant leukocytes and their use in the treatment of cancers and viruses

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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006097337A2 (fr) * 2005-03-18 2006-09-21 Onepharm Gmbh Inhibiteurs de la 11$g(b)-hydroxysteroide deshydrogenases
WO2006097337A3 (fr) * 2005-03-18 2007-08-23 Bionetworks Gmbh Inhibiteurs de la 11$g(b)-hydroxysteroide deshydrogenases
US7759339B2 (en) 2005-03-31 2010-07-20 Takeda San Diego, Inc. Hydroxysteroid dehydrogenase inhibitors
WO2007025892A1 (fr) 2005-08-31 2007-03-08 F. Hoffmann-La Roche Ag Inhibiteur de la 11-bêta-hydroxystéroïde déhydrogénase-1 des diabètes de type 2-1
US7622492B2 (en) 2005-08-31 2009-11-24 Hoffmann-La Roche Inc. Pyrazolones as inhibitors of 11β-hydroxysteroid dehydrogenase
WO2010047982A1 (fr) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Nouveaux dérivés de benzimidazole cycliques utiles comme agents anti-diabétiques
WO2010051206A1 (fr) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Nouveaux agents antidiabétiques utiles avec des dérivés de benzimidazole cycliques
WO2011106273A1 (fr) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Nouveaux dérivés benzimidazole cycliques utiles comme agents antidiabétiques
WO2012116145A1 (fr) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
EP3243385A1 (fr) 2011-02-25 2017-11-15 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
WO2014022528A1 (fr) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2014130608A1 (fr) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Composés bicycliques antidiabétiques
WO2014139388A1 (fr) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Nouveaux dérivés d'indole utiles en tant qu'agents antidiabétiques
WO2015051725A1 (fr) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2018106518A1 (fr) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Composés hétérocycliques antidiabétiques
WO2018118670A1 (fr) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Composés de spirochromane antidiabétiques
WO2019186171A1 (fr) * 2018-03-28 2019-10-03 Benevolentai Bio Limited Traitement des maladies sarcopéniques
EP3878446A1 (fr) 2020-03-09 2021-09-15 Universite De Geneve Inhibiteurs hsd11b1 pour utilisation en immunothérapie et leurs utilisations
WO2021180643A1 (fr) 2020-03-09 2021-09-16 Universite De Geneve Inhibiteurs de hsd11b1 destinés à être utilisés en immunothérapie et leurs utilisations

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US20040138258A1 (en) 2004-07-15

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